Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Pathology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.
Elife. 2021 Feb 10;10:e61798. doi: 10.7554/eLife.61798.
While transcripts of neuronal mitochondrial genes are strongly suppressed in central nervous system inflammation, it is unknown whether this results in mitochondrial dysfunction and whether an increase of mitochondrial function can rescue neurodegeneration. Here, we show that predominantly genes of the electron transport chain are suppressed in inflamed mouse neurons, resulting in impaired mitochondrial complex IV activity. This was associated with post-translational inactivation of the transcriptional co-regulator proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In mice, neuronal overexpression of , which encodes for PGC-1α, led to increased numbers of mitochondria, complex IV activity, and maximum respiratory capacity. Moreover, -overexpressing neurons showed a higher mitochondrial membrane potential that related to an improved calcium buffering capacity. Accordingly, neuronal deletion of aggravated neurodegeneration during experimental autoimmune encephalomyelitis, while neuronal overexpression of ameliorated it. Our study provides systemic insights into mitochondrial dysfunction in neurons during inflammation and commends elevation of mitochondrial activity as a promising neuroprotective strategy.
虽然神经元线粒体基因的转录物在中枢神经系统炎症中受到强烈抑制，但尚不清楚这是否导致线粒体功能障碍，以及增加线粒体功能是否可以挽救神经退行性变。在这里，我们表明，在炎症小鼠神经元中主要抑制电子传递链的基因，导致线粒体复合物 IV 活性受损。这与转录共调节剂过氧化物酶体增殖物激活受体γ共激活因子 1-α（PGC-1α）的翻译后失活有关。在小鼠中，神经元过表达编码 PGC-1α 的 ，导致线粒体数量增加、复合物 IV 活性和最大呼吸能力增加。此外，过表达 的神经元显示出更高的线粒体膜电位，与改善的钙缓冲能力有关。因此，实验性自身免疫性脑脊髓炎期间神经元中 的缺失加剧了神经退行性变，而神经元中 的过表达则减轻了这种情况。我们的研究为炎症期间神经元中线粒体功能障碍提供了系统的见解，并推荐提高线粒体活性作为一种有前途的神经保护策略。
